Neurotrophins are peptide growth factors best studied for their roles in promoting neuronal survival and axonal growth in the developing nervous system. However, neurotrophins have also been implicated in development and function of several non-neuronal tissues including the cardiovascular, immune and endocrine systems. In the pancreas, in vitro studies have shown that the neurotrophin, Nerve Growth Factor, (NGF) regulates survival and function of insulin-producing [unreadable]-cells. NGF also prolongs survival of transplanted mouse islets in vitro and in vivo. These studies implicate NGF signaling in pancreatic islet development and regeneration. However, to date, there have been no attempts to use genetically modified mice lacking NGF or its receptor tyrosine kinase, TrkA, to address the in vivo role of neurotrophin signaling in the pancreas, and specifically islet development. Employing mice deficient for NGF, we observed that developing pancreatic islets are disorganized and that the normal spatial arrangement of endocrine cell types within islets is disrupted. In adult heterozygous NGF+/- mice, pancreatic islets are reduced in size and fragmented. Since NGF and its receptor, TrkA, are expressed in islet cells, these deficits could arise due to a direct requirement for NGF signaling in the pancreas or indirectly due to the death of NGF-dependent neurons innervating the pancreas. Based on our preliminary results, the goal of this proposal is two-fold;(1) Use genetically engineered mouse models to examine the cell-autonomous requirement for NGF-TrkA signaling in islet development, and (2) determine the contribution of sympathetic neurons to pancreas development by employing a combination of in vitro neuron-pancreas co-culture assays and in vivo analyses of pancreas development in mutant mice lacking sympathetic innervation. By focusing on the in vivo requirement for neurotrophin signaling and nerve-derived signals in pancreas development, our studies will provide unique insight into extrinsic growth factors that regulate pancreas development. Knowledge about extrinsic signals regulating islet development will facilitate the design of better therapeutic strategies to promote islet survival during type I diabetes and injury, as well as enhance islet survival following transplantation. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to identify novel extrinsic growth factors that influence development of pancreatic islets. Gaining insight into extrinsic signals regulating islet development has important implications for treatment of type I diabetes, promoting pancreatic regeneration following injury or disease, and prolonging islet survival after transplantation. In this study, we focus on the neurotrophin, Nerve Growth Factor (NGF), a soluble growth factor best studied for its role in promoting neuronal survival and connectivity in the developing nervous system. NGF and its receptor, TrkA, are also expressed in the pancreas and NGF signaling has been shown to promote survival of pancreatic islet cells, in vitro. However, to date, there have been no attempts to use genetically modified mice to address the in vivo role of NGF signaling in the pancreas and specifically islet development. The goal of this study is to use innovative tools including mouse genetics and neuron-pancreas co-cultures to address whether NGF signaling influences pancreas development directly by signaling within the pancreas, or indirectly via promoting innervation of NGF-responsive sympathetic neurons. Together, these studies will provide significant insight into a previously uncharacterized question of the influence of neurotrophins and nerve-derived signals in islet development.